When is MRSA not MRSA?

...when it contains a weird gene conferring methicillin resistance that many tests miss.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a big issue in the past 15 years or so, as it turned up outside of its old haunts (typically hospitals and other medical facilities) and started causing infections--sometimes very serious--in people who haven't been in a hospital before. Typically MRSA is diagnosed using basic old-school microbiology techniques: growing the bacteria on an agar plate, and then testing to see what antibiotics it's resistant to. This can be done in a number of ways--sometimes you can put a little paper disc containing antibiotics right onto a plate where you've already spread out a bacterial solution and see which discs inhibit growth, or sometimes you can grow the bacteria in a plate with increasing concentrations of antibiotics, to see when the drugs are high enough to stop growth. Both look at the phenotype of these bacteria--the proteins they're expressing which lead to the bacteria's drug resistance.

However, these culture-based methods are slow--they can take days between when the patient first is seen by a doctor and the time the results come back from the clinical lab. For this reason, increasingly labs are moving to molecular methods, which are much quicker than the culture-based methods. Indeed, detection of the gene responsible for methicillin resistance, mecA, has been the gold standard for *really* identifying MRSA, even beyond phenotypic methods.

A new pairof papers demonstrate the limitations of this reliance. Like many science discoveries, this one started with a "huh, weird" moment. Investigators noticed that a number of their S. aureus samples were categorized as MRSA using the traditional phenotypic methods, but were negative when it came to the mecA DNA test. Genetic analysis showed that these isolates carried a different mecA gene, dubbed mecALGA251. The investigators searched their isolate collection in England, and also worked with collaborators in Scotland and Denmark to search through their banks for additional mecA-negative MRSA, and found almost 70 isolates, including one dating back to 1975. (A second paper by a different group examined two isolates in Ireland).

Now is when it starts to get really interesting. (Continued below)

Many of the isolates from England were of cattle origin--from milk samples. When these were typed, most of them were the same spa type (a way to type S. aureus, sequencing a repetitive region of the Protein A gene, which encodes a surface protein). These were t843. Why is this interesting? Because t843 is considered to be a "cattle" type of S. aureus. So sure, it makes sense that you'd find it in milk samples--that's a no-brainer. But it was also found in human samples in England, Scotland, and Denmark (including that previously-mentioned human isolate from 1975). A second paper also found t843 in a patient from Ireland, along with a closely-related spa type in a second patient (t373). What is this "cattle" strain doing infecting humans? The authors draw parallels to the emergence of the "pig" strain of S. aureus, ST398, that has also been found in humans and other animals (including dogs, horses, rats, and chickens). Is this another "animal" strain that's emerging in humans? Or is it a human strain that we've given to cattle, like we did with chickens? The types found in humans and milk samples in the same areas match pretty nicely between humans and cattle (shown below, Figure 2 in the manuscript), suggesting local interspecies transmission.

Looking over time, they also noted that the prevalence of this odd mecA gene increased over time in their database (2007-2010). It's still low--less than 1% of the samples--but what was also unique was that it was in other lineages besides the t843 strains. As in, at least 3 different lineages besides the one containing t843. So, it looks like this weird mecALGA251 gene is jumping around, inserting itself into all kinds of methicillin-susceptible S. aureus. ("Regular" mecA does this too so that wasn't completely shocking, but it was a surprise that it's had enough time to spread to 4 different lineages without ever being detected).

Where does this leave us? We have to be careful and make sure we don't outsmart ourselves with our technology. For now, the benefits of using DNA-based identification methods still outweigh risks of missing weird MRSA since its prevalence is fairly low, but we need to be cognizant of the potential to miss isolates, and keep backing up our molecular methods with old-school cultures. We also need to periodically adjust our "gold standard" molecular tests to include novel findings like this new mecA. The authors note that in addition to their new findings, they also found several isolates "that had an MRSA phenotype but no mecA gene that could be detected by PCR (polymerase chain reaction)"--so there might be other unique mecA genes (or other resistance mechanisms) that remain undiscovered.

Finally, this paper again makes me ever so jealous of the surveillance systems in other countries. In Denmark, for example, all MRSA are to be submitted to the Statens Serum Institut, where they type all of them. Now sure, Denmark is much smaller than the U.S., but even to have this type of surveillance state-wide is incredibly difficult here. Trying to compare between states? Even harder. So--do we have these strains here? Probably so, but it will be more hit-or-miss to find them.

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Great post on this interesting issue. Having been trained in classical microbiology, I have always been leery of over-dependence on genetic methods. Functional studies, even if they take a longer time, make more sense to me - and here is the perfect example: I would not hesitate to call an MRSA 'MRSA' if it grows comfortably in presence of methicillin; the presence of the mecA gene is predictive and corroborative, but not definitive - until the whole Staph genome is mapped AND the functionalities of its genes defined.

Yes, I do understand the benefits of DNA-based identification, before anyone asks, heh-heh! :) But functional correlations of genetic features are important, as these studies show.

As a side note to Tara regarding her final remark: I completely concur. At times it can be quite frustrating - from personal experience. In the US, it seems so difficult to get agencies to talk to each other. There are egos to soothe, politics to manage, turf-wars to steer around, and so forth. Doing any kind of surveillance studies from an academic institution requires pushing mountains while standing on tippy-toes.

Interesting. Now imagine that DNA testing becomes the dominant way to decide which antibiotic to use. Won't bacteria then be under selective pressure that favors "decoy" mutations that point to the wrong antibiotic?

We used to laugh at the Doc's who'd come to the lab and order stat micro results. Obviously, not to their face, beings it was in the Navy and all. But, it was hard not to. Their rank caused them to believe they were smarter than the lab tech and if they just yelled long enough, the tech would have to produce results. Having said that DNA testing has, from all reports I've heard been a real boon to medical treatment. Can some protocol be developed that would guide when testing should be done with both DNA and agar? I'm obviously rusty and perhaps I've missed something but it would seem that some standard being in place would be highly beneficial.

The molecular tests can be modified to include these new mec types--either by adding a second set of primers, or redesigning the old ones so that they will be inclusive of the more diverse types. So yes, I don't think they will be going away anytime soon due to their speed, but their limitations need to be remembered by those who use them.

Well, the era of relatively cheap whole-genome microbial DNA sequencing has arrived, so 'gold standard' typing tests based on sequence analysis of one or a few genes will soon be as obsolete as using plates of nutrients and antibiotics to determine strain type. This doesn't mean these methods should be abandoned, but in terms of determining relatedness, whole-genome approaches are far superior.

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